Substituted 1, 4, 4a, 9, 9a, 10-hexahydro-4, 10-dioxoanthracenes



United States. Patent This invention relates to new organic compoundsand, more particularly, is concerned with novel substituted1,4,4a,9,9a,10-hexahydro-4,IO-dioxoanthracenes and to novel methods ofpreparing these compounds. The novel substituted 1,4,4a,9,9a,10hexahydro-4,lO-dioxoanthracenes of the present invention may berepresented by the following general formula:

wherein X is halogen, R is hydrogen or lower alkyl, and Z is hydroxy,halogen, lower alkoxy, phenyl lower alkoxy, amino or substituted amino.Suitable lower alkyl and lower alkoxy groups contemplated by the presentinvention are those having up to about six carbon atoms. Suit ablephenyl lower alkoxy substituents are, for example, benzyloxy andphenethoxy. Halogen is exemplified by chlorine and bromine. Suitablesubstituted amino groups are, for example, methylamine, dimethylamino,ethylamino, diethylamino, piperidino, morpholino, pyrrolidino andN-methylpiperizino.

The novel compounds of the present invention are particularly useful aschelating, complexing or sequestering agents for polyvalent metallicions. The complexes formed with polyvalent metallic ions areparticularly stable and usually quite soluble in various organicsolvents. This, of course, makes them useful for a variety of purposessuch as in biological experimentation where the removal of traces ofpolyvalent metallic ions may be of great importance. They are alsouseful in analyses for polyvalent metallic ions which may be complexedand extracted by means of these reagents. Other uses common tosequestering agents are also apparent from these compounds.

The novel compounds of the present invention are obtainable ascrystalline materials having characteristic melting points andabsorption spectra. They are appreciably soluble in many organicsolvents such as lower alkanols, acetone, ethyl acetate, and the like.ever, generally insoluble in water. The novel compounds of the presentinvention are biologically active and have been found to possessantifungal activity. The minimal inhibitory concentrations, expressed ingammas per milli liter, of three typical compounds of the presentinvention against Staphylococcus aureus when measured by; a standardturbidimetric procedure are 'set forth in the following table. TABLE I-Minimal inhibitory Compound: conc. in. 'y/rnl.

Benzyl hydroxy 8 chloro 1,4,4a,9,9a,

hexahydro 1 4,10 dioxoan-thr acene 3- carboxylate 0.279 Ethyl 5 hydroxy8 chloro 1,'4,4a,9,9a,10- hexahydro 4,10 dioxoanthracene-3-cari boxylate0.189 5 hydroxy 8 chloro 1,4,4a,9,9a,l0 hexa- =hydro 4,10dioxoanth-racene 3 carboxamide 0.550

They are, how

Cit

The novel compounds of the present invention are prepared by a series ofreactions starting with the appropriately substituted1,2,3,4-tetrahydro-4-oxo-2-naphthaleneacetaldehydes disclosed andclaimed in the copending application of Raymond G. Wilkinson et 211.,Serial No. 821,- 093, filed June 18, 1959, now Patent No. 3,102,914. Theseries of reactions leading to the novel compounds of the presentinvention may be represented by the following reaction scheme:

| GHT-CHO OH -CH:C I

0R (in COzRl COzR;

' -OOR2 (BR I 0 or: ii H6 CORZ (VIII) wherein R is hydrogen or loweralkyl, R is lower alkyl or phenyl lower alkyl, R is amino or substitutedamino, and X is halogen. Suitable lower alkyl groups contemplated by thepresent invention are those having up to about six carbon atoms.Suitable phenyl lower alkyl substituents are, for example, benzyl,phenethyl, etc. Halogen is exemplified by chlorine and bromine. Suitablesubstituted amino groups are, for example, methylamino, dimethylamino,ethylamino, diethylamino, piperidino, morpholino, pyrrolidino andN-methylpiperizino.

In accordance with the present invention, an appropriately substituted1,2,3,4 tetrahydro 4 oxo-2-naphare thaleneacetaldehyde (I) is firstconverted to the corresponding 1,2,3,4tetrahydro-4-ox-o-2-naphthylethylidene malonic ester. (II) by treatmentwit-h a di (lower .alkyl) or di(phenyl lower alkyl)ester of malonicacid, conveniently diethyl mal-onate or dibenzyl malonate. This malonicester isthen subjected to a Diels Alder condensation withcyclopentadiene whereby the corresponding cyclopentadiene adduct (III)vis obtained. This Diels-Alder condensa-tio-n isfco'nve'niently carriedout in an inert organic solvent such as toluene or xylene, but a solventmay be omitted. Elevated temperatures up to about 150 C. and a period oftime up to about 48 hours may be needed to complete the condensation.

The cyclopentadiene adduct is then cyclized to the corresponding 1,4,11,1 1 a, 1'2,1zaahexahydro-5-hydroxy-6-oxo-1,4-mthan-onaphthacene-4a(6H)-carboxylate (IV) with a strongly basiccondensing agent such as an alkali metal hydride, an alkali metalalkoxide, an alkali metal amide or an alkali metal triphenyl methide ina neutral anhydrous solvent such asbenzene, toluene, xylene, or thelike, at a temperature of from 50 C. to 150 C. The 1,4,11,1la, 12,12ahexahydro 5 hydroxy-6-oxo-1,4-methanonaphthacene-4a(6H)-carboxylate isthen thermally decomposed to the corresponding1,4,4a,9,9a,10-hexahydro-4,10- dioxoanthracene-3-carboxylate (V). Thisthermal decomposition occurs when a pentacyclic intermediate of thepresent invention is maintained at a temperature above 110 C.,conveniently at the reflux temperature of an inert organic solvent suchas o-dichlorobenzene, Decalin, or the like, for a period of time rangingfrom about 15 minutes up to about one hour.

Alternatively, the pentacyclic esters (IV) may be saponified to yieldthe corresponding pentacyclic acids (VI) which, in turn, may beconverted to the corresponding pentacyclic acid halides (VII) bystandard procedures. Both the pentacyclic acids (VI) and thepentacyc-lic acid halides (VII) may be reconverted to pentacyclic esters(IV) of choice by standard 'esterification procedures.

The pentacyclic acid halides (VII) may be thermally decomposed to thecorresponding l,4,4a,9,9a,l-hexahydro- 4,10-dixbanthracerie-3-carboxylhalides (1X) under the same conditionsset forth above for the thermaldecomposition of the pentacyclic esters (IV). The 1,4,4a,9,- 9a,10hexahydro 4,10 dioxoanthracene 3 carboxylhalides (IX) may be convertedeither to the corresponding1,4,4a,9,9a,l0-hexahydro-4,10-dioxoanthracene-3-carboxylates (V) bystandard esterification proceduresor to the corresponding1,4,4a,9,9a,10-hexahydro-4,1'0-dioxo anthracene-3 carb0xamides (X) bystandard amidation procedures. The pentacyclic acid halides (VII). maybeconverted to the corresponding pentacyclic amides (VIII) by standard'amidation procedures. The pentacyclic amides (VIII) may then bethermally decomposed to the correspondingl,4,4a,9,9a,10-hexahydro-4,10=dioxoanthracene-3-carboxamides (X) underthe same conditions set forth above for the thermal decomposition of thepentacyclic esters (IV).

The invention will be described in greaterdetail in conjunction with thefollowing specific examples.

EXAMPLE 1 Dieihyl 8-chlor0 1,2,3,4-tetrahydro--methovcy-4-oxm2-naphthylethylidene malonate useof a water separator until no more waterwas pro- 7 duced by the condensation (two hours). After an additionalBO'minutes of refluxing the cooled reaction mixture was washed withdilute aqueous hydrochloric acid, then with dilute aqueous sodiumbicarbonate solution, and finally with water. The organic layer wasseparated and EXAMPLE 2 'Diethyl8-clzlor0-1,2,3,4-tetrahydro-5-hydroxy4-oxo-2- naphthylethylidenemalonate A solution of 16.0 g. of 5-hydroxy-8-chloro-1,2,3,4-tetrahydro-4-oxonaphthalene-2-acetaldehyde, 10.0 ml. of diethylmalonate', 0.8 ml. of glacial acetic acid, and 0.4 ml. of pipe'ridine in50ml. of dry benZene-was brought to gradual reflux under ,a nitrogenatmosphere. The reactioh mixture was slowly and partially distilled withthe use of a water separator until no more water was produced by thecondensation (about 2 hours). After an additional 30 minutes ofrefluxing the product was isolated according to the procedure of Example1.

EXAMPLE 3 Dibenzyl 8-chl0r0-1,2,3,4-tetrahydro-S-hydr0xy-4-ox0-2-naphthylethylidene malonate A solution of 1.9 g. of5-hydroxy-8-chloro-1,2,3,4-tctrahydro 4-oxonaphthalene-2-acetaldehyde,2.4 g. of diben- Zyl malonate, 0.2 ml. of glacial acetic acid, and 0.06ml. of piperidine in 50 m1. of dry benzene was brought to gradual refluxunder a nitrogen atmosphere. The reaction mixture was slowly andpartially distilled with the use of a water separator until no morewater was produced by the condensation (about 2 hours). After anadditional 30 minutes of refluxing, the product was isolated accordingto the procedure of Example 1.

EXAMPLE 4 Cyclopentadiene adduct of diethyl8-chl0ro-1,2,3,4-tetrahydro-S-methoxy-4-0x0-2-naphthylethylidenemqlonafe A mixture or 6.3 g, o diethyl s-' -.;111 m--1',2,3,4-tetrahydro-5-methoxy-4-oxo-2-naphthylethylidene malonate and5.0 of cyclopentadiene in 12 inl. er dry toluene was placed in a glassliiied bomb and held sealed at 135-140" C. for 16 hours. Removal ofsolvents by evaporation under vacuum gave the product-in crude term.

EXAMPLE 5 Cyclopentadiene adduct of diethyl 8-chl0r0'-1,2,3,4-tetrahydro-S-hydroxy-4-oxo-2-naphthylethgylidn'e malonhte A mixture of10.5 g. of. diethyl 8-chloro-l,2 ,3,4-tetrahydro J5 hyd'r'oxy 4 oxo 2naphthylethylide'ne malonate and 11.0 ml. of cyclopen't'adi'ehe in 70ml.of dry toluene was placed in a glass-lined bomb and held sealed at135140 C. for 16 hours. Removal of solvents by evaporation under. vacuumgave the product. in crude form.

EXAMPLE 6 A mixture of 3.99 ggOfdlbQIlZYl8-Ch10lO-1,2,3.,4*t6t18.=hydro-S-hydroxy-4-oxo-2-napl1thylethylidene malona'te and 4.0 ml. offreshly distilled 'cyclopentadiene in 5.0 ml. of toluene was placed in aglass-lined bomb and held sealed at 135l40 C. for 16 hours. Removal ofsolvents by evaporation under vacuum gave the: product in crude form.

Ethyl 1 O-chloro-I ,4,11,1 1a,12,1Za-hexahydrowli-hydroxyimethoxy- 6axe-1 ,4-ii1et7zdnonaphthacenela(6H -.car-

boxylare The crude product of Example 4 was dissolved in ml.'of toluene.and to this solution'was added 8.5 g. of

50% sodium hydride in mineral oil. The resulting mixture was" stirredunder a nitrogen atmosphere at refluxtemperature for 65 minutes. Thecooled reaction mixture was neutralized by the gradual addition ofexcess glacial acetic acid, followed by dry ethanol. After dilution with100 ml. of ethyl acetate and 200 ml. of 1 N hydrochloric acid, theorganic layer was washed with water, dried and evaporated under vacuumto a tan oil. This oil, the pentacyclic ethyl ester product, wascharacterized by ultraviolet maxima at 353 and 262 nm in methanolsolution, andat 368 and 262 mu in methanolic 0.01 N sodium hydroxidesolution.

EXAMPLE 8 Ethyl 10-chl0r0-1,4,1l,11a,12,12a-hexahydr0 5,7 dillydrxy-60x0-1,4-methan0nwphthacene-4w(6H)-carb0xylate I This product wasprepared according to the procedure of Example 7, using as startingmaterial the crude product of Example 5. The pentacyclic ethyl ester wasisolated in the form of yellow needles, M.P. 172173 C. The product wascharacterized by ultraviolet maxima at 369, 351, 271 and 227 m inmethanol solution.

EXAMPLE 9 Benzyl 10-chl0r0-1,4,11,11a,12,12ahexahydro 5,7-dihydr0xy-6oxo-I,4-methanonaphthacene-4w(6H) -carb0xylate This product was preparedaccording to the procedure of Example 7, using as starting material thecrude product of Example 6. The pentacyclic benzyl ester product wasisolated in the form of a gum. Chromatography over 50 g. of silica gel,using 70% benzene-30% petroleum ether as eluant, gave 1.25 g. of a gumwhich, upon crystallization from ether, deposited 0.3 g. of yellowcrystals,

M.P. 169-172 -C., of the pentacyclic benzyl ester product.

EXAMPLE l0 Ethyl 5-meth0xy-8-chl0r0-1,4,4a,9,9a,10-hexahydro-4,10-dioxoanthracene-3-ca rboxylate 0.01 N sodium hydroxide solution.

EXAMPLE 1l Ethyl 5-hydroxy-8-chl0r0-1,4,4a,9,9a,10-hexahydr0-4,10-dioxoanthracene-S-carboxylate Thirty mg. of ethyl-chloro-l,4,11,1la,l2,l2a-hexahydro-5,7 dihydroxy-6-oxo-l,4methanonaphthacene-4a- (6H)-carboxylate, the product of Example8, was thermally decomposed according to the procedure of Example 10.The isolated product was recrystallized from ether to give orange-yellowcrystals of ethyl 5-l1ydroxy-8-chloro- 1,4,4a,9,9a,10-hexahydro-4,l0dioxoanthracene-3-carboxylate, M.P. 131 C.

EXAMPLE 12 Benzyl 5-hydroxy-8-chloro-1,4,4a,9,9a,10-hexahydr0-4,10-dioxoanthracene-3-carb0xy[are Two hundred mg. of be'nzyl10-chloro-1,4,11,11a,12,- 12a-hexahydro5 ,7dihydroxy-6-oxo-1,4-methanonaphthacene-4a(6H)-carboxylate, the productof Example 9, was thermally decomposed according to the procedure ofExample 10. There was thus obtained 85 mg. of the desired product, M.P.137138 C.

EXAMPLE 13 1 0-chl0r0-1,4,11,1 1 L1,] 2,12a-hexahydro-5,7-dihydroxy-6-0x0-1,4-methan0naphthacene-4a(6H) -carboxylic acid EXAMPLE l410-chl0r0-1,4,1 1,1 1a,12,12a-hexahydr0-5,7-dihydroxy-6-oxo-l,4-metharz0naphthacene-4a (6H) -carboxylic acid Ethyl10-chloro-1,4,l 1,11a,l2,l2a-hexahydro-5,7-dihydroxy-6-oxo- 1,4methanonaphthacene-4a(6H)-carboxylate, 0.090 g., was saponifiedaccording to the procedure of Example 13 to yield the same product, M.P.172-174 C.

EXAMPLE 15 10-chl0r0-1,4,1 Z ,1 1a,12,1Za-hexahydro-S,7-dihydr0xy-6-oxo-J ,4-methmz0naphthacene-4a(6H -carbonyl chloride To a suspension of54 mg. of 10-chloro-l,4,11,11a,12, 12a-hexahydro 5,7dihydroxy-6-oxo-l,4-methanonaphthacene-4a(6H)-carboxylic acid in 2 ml.of dry benzene was added 3 mg. of dimethyl formamide and then 0.20 ml.of freshly-distilled thionyl chloride. The reaction mixture was stirredat room temperature under a drying tube for 45 minutes, by which timecomplete solution had occurred. The mixture was diluted with 20 ml. ofdry benzene and evaporated to dryness in vacuum at room temperature.There were obtained, as the residue, 57 mg. of the yellow crystallineacid chloride, having the characteristic carbonyl maximum near 5.60 inthe infrared spectrum.

EXAMPLE l6 5-hydr0xy-8-chl0r0-1,4,4a,9,9a,10-hexahydr0-4,10-

dioxoanthracene-3-carboxamide A benzene solution of10-chloro-1,4,11,11a,l2,12ahexahydro-5,7-dihydroxy 6 oxo 1,4methanonaphthacene-4a(6H)-carbonyl chloride, prepared from 11 mg. of thecorresponding acid by the method of Example 15, was saturated with drygaseous ammonia for ten minutes at room temperature. Cold dilutehydrochloric acid was then added, the organic layer was diluted withethyl acetate, washed with dilute acid and then with water. Afterdrying, the solvents were removed in vacuo to give the pentacycliccarboxainide. This intermediate was dissolved in 5 ml. ofo-dichlorobenzene' and the solution refluxed in a nitrogen stream for 15minutes. Evaporation of solvent gave 3 mg. of the crystalline S-hydroxy-8-chloro-1,4,4a,9,9a,10-hexahydro 4,10 dioxoantharacene-3-carboxamide,characterized by amide carbonyl abserption at 5.90 in the infrared andultraviolet absorption at 393 mg in methanol.

What is claimed is:

1. A compound of the formula:

I II II 0 0R 0 0 wherein X is selected from the group consisting ofchlorine'and bromine; R is selected from the group consisting ofhydrogen and lower alkyl; and Z is selected from the group consisting oflower alkoxy and phenyl lower alkoxy.

2. Ethyl S-methoxy-S-chloro-l,4,4a,9,9a,10-hexahydro-4,lO-dioxoanthracene-3-carboxylate.

mula:

l 1 b OR wherein X is selected from the group consisting of chlorine,and bromine; R is selected from the group consisting of hydrogen andlower aikyl; and Z is selected from the group consisting of loweralk'oxy and phenyl lower alkoxy; which comprises treating a1,2,3,4-tetrahydro-4-oxo-2- naphthaleneacetaldehyde with :a malonicester to form the corresponding 7l,2,3,4-tetrahydr0-4-oXo-2-naphthylethylidene malonate, treating saidmalonate with cyclopentadiene to form the corresponding cyclopentadieneadduct, treating said adduct with a strongly basic cyclizing agent underanhydrous conditions to form the corresponding 1,4,11,11a,12,12ahexahydro-5-hydroxy-6-oxo-1,4-'nethanonaphthacene-4a(6H)-carboxylate,and thermally decomposing said carboxylate at a temperature above 100 C.

References Cited by the Examiner UNITED STATES PATENTS 12/61 Fields eta1 260-473 OTHER REFERENCES Muxfeldt:- Ber. Deut. Chem., volume 92, page3130 (i959).

Muxfeldt et al.: 16088d (1959).

Chem. Abstracts, volume 53, page LORRAINE A. WEINBERGER, PrimaryExaminer.

DUVAL MCCUTCHEN, LEON ZITVER, LORRAINE A. WEINBERGER, Examiners.

1. A COMPOUND OF THE FORMULA: